Micropulverized therapeutic agents



Dec. 5, 1950 G..v. TAPLIN Er AL MICROPULVERIZED THERAPEUTIC AGENTS FiledMarch 8, 1947 A sur! IN V EN TOR. GEORGE l( MPL/N FREDERICK A. BRYAN ATTORNEY Patented Dec. 5, 1,950

MICROPULVERIZED 'THERAPEUTIC AGENTS George V. Taplin and Frederick A.Bryan, Brighton, N. Y.

ApplicationMarc'n 8, 1947, Serial N0. 733,280

Claims. l

The present invention relates to therapeutic agents and to a method foradministering the same. ln particular, the invention relates toabsorbable therapeutic agents which vcan be produced in powdered form.

The invention is applicable .to the preparation and administration of.any absorbable therapeutic agent, such as, for instance, penicillin,streptomycin, any of the sulfonamides, adrenalin, Tuamine, Neosynephrineetc., whether used singly er in combination. For the purpose of anunderstanding the invention, however, it will be described specificallyirst in vconnection with the preparation and administration .ofpenicillin. The wide variety of uses, to which the invention may be putwill be pointed out more in detail hereinafter.

Hereteiore, one common way of administering penicillin has been bynebulizing a penicillin solution and inhaling the spray or vapor soproduced. This method of administeringzpenicillin, which is known as the.aerosol principle, has,

however, many disadvantages.

`oxygen ymust be connected to the atomizer or nebulizer. While tanks ofoxygen are relatively easy to procure in afhospital, they are hard toget for use in the home. Moreover, they are an expensive means forproducing the pressure sufficient to form a spray. They add materially,also, to the weight and cumbersomeness of the nebulizer. Hand pumping,on the other hand, is a long, tedious operation. it may take Vonequarterto three-quarters of an hour to administer a treatment of the requirednumber of units of penicillin with a manually operated spray. Even withthe oxygen tank, it'takes 15 to 20 minutes to administer the requireddosage. The length of time required to administer a dose is very tiringto the patient and often the irritation and nervous tension to which thepatient is sub- Vjected during the long period required foradministering the drug offsets to a large extent the benecial effects ofthe dosage.

Furthermore, the aerosol method 'of administration is inefficient and.wasteful. Fora treatment of twenty-ve thousand to'fty thousand units ofpenicillin, fty thousand to one hundred thousand units may have to :beemployed; so

-much of the penicillin-is dissipated vand lost in the air in the spray.In order that the patient Amay obtain the required numberof units ofpenicillin in a day,then, fourmor five vdoses per day may have to beadministered.

A further drawback of the aerosol method of administration is theinstability of penicillin in solution. Penicillin solutions deterioraterapidly, and must be kept refrigerated to vretain their full potency foreven a week.

.One object of the present invention is tozprovide a new form in whichtherapeutic agents, such as penicillin, can be produced, to enable lsuchsubstances to be :administered much more rapidly and much more eicientlythan heretofore.

Another object of the invention is to provide a yform in whichtherapeutic agents may be administered, which will be stable and whichcan with ease be so preserved as to retain more or less indefinitely thepotency of the agent.

Another object of the invention is to provide a simple method foradministering therapeutic substances whereby the required :dosage can besupplied in an extremely short period oi time, and eortlessly so'far as.the patient is concerned.

:A further object of the invention is to provide simple, inexpensiveapparatus for administering therapeutic agents in powdered form.

Still anotherfobject of the invention is to provide a piece of apparatusfor administering theraeutic substances, which will be light in weightand of a size that can readily be carried-around in the pocket of apatient.

A still further object of the invention is to provide a piece ofapparatus for administering therapeutic substances, which is simple inconstruction, quite inexpensive, and which can readily be operated bythe patient himself without eifort.

Other objects ofthe invention willbe apparent hereinaiter from thespecication and fromthe rec-ital of the appendedclaims.

lt is well known that penicillin can be produced in crystalline form,but heretofore the-crystals of penicillin have been dissolved in asaline solution and the penicillin administered, as already described,in the form of a vapor. Thepresent invention is based on the use ofpenicillin and other soluble therapeutic agents in the formof powder,and upon the administration of the agent by particulate suspensionof theagent in air, Vso that a powder smokeis produced, which can be Vinhaledor applied topically. The'powdered penicillin can rbe obtained bygrinding crystalline penicillinin a ball-mill or other suitableapparatus to a powder with Aa.particulate-size of less than one micron.Thus the powder particles are of the approximate size or may be evensmaller than the size of the droplets produced by a nebulizer.

It has been found that when micro-pulverized penicillin is administeredby particulate suspension in air, a dose of twenty-ve thousand to tythousand units ci penicillin can be administered in one or two minutesor less. Moreover, the powdered penicillin can easily be carried in anair stream produced by simple inhalation through the mouth or bypressure on an ordinary rubber air bulb. The administration of thepenicillin or other therapeutic agent in the novel form of the presentinvention can be effected therefore without effort; and there is no needfor the use of oxygen or any other mechanical source or pressure. It hasbeen found, too, that when penicillin is administered in this way, theeiiciency of 'the dosage is 93 to 95 per cent, so that the cost and thenumber oi dosages are reduced very considerably from those heretoforerequired.

Moreover, since there are seventy square meters of surface in the lungs,the very line particles of penicillin supplied to the lungs by thepresent method are absorbed quickly and over so great an area that adosage or" penicillin administered according to the present invention isextremely effective, so that the disease, for which the dosage ofpenicillin is prescribed, can be brought under control much more quicklythan by previous methods oi administration. Aside from the local actionof the penicillin on the lungs, it is picked up quickly by the bloodstream.

Because of the high potency or" pure penicillin, it has been founddesirable in practice to mix the penicillin with anhydrous glucose or asimilar Vehicle in the proportion of 1 5 to 1 26 and to grind themixture together to a powder. This mixture provides an inexpensive, buteiective therapeutic agent, and when inhaled in the form of a smokeproduces practically no bronchial irritation, while the taste is a mixedone of faint bitterness and sweetness. Because of its glucose content,moreover, the mixture is additionally benecial to a patient.

In the apparatus for administering the powdered penicillin, it isdesirable to provide two chambers, which are connected together. In therst of these chambers, which is that through which the air passes first,there is provided some substance which will absorb the moisture out ofthe air, so that the air will be dry when it passes into the secondchamber, which contains the penicillin powder. This moisture absorbingsubstance may be anhydrous calcium sulfate or a similar substance, andthis may be mixed with a litmus-type indicator which will show by changeof color when the dehydrating material has picked up all of the moistureit can hold. Various such materials are well known and are soldextensively under different trade-names.

It is also within the contemplation of the invention, however, to use adisposable container containing a single specic dose of the therapeuticagent. This container, which may be made of papier-mache', is providedwith inlet ducts through which air is admitted to the powder chamber andan outlet duct through which the powder in suspension may be inhaledthrough the nose or mouth. The container is intended to be sold with thedose in it and with the dose protected against moisture by an airtightcovering which encloses the whole container. This covering is rippedaway when the dose is to be used, and the container is intended to bethrown away after use.

In the drawings:

Fig. 1 is a sectional view of a piece of apparatus built according toone embodiment of this invention for administering a therapeutic agent,and having an air bulb for producing the air stream that picks up thetherapeutic powder;

Fig. 2 is a sectional view of the apparatus shown in Fig. 1, butillustrating how, by removal of the air bulb, the apparatus may beemployed for inhaling the therapeutic substance through the mouth;

Fig. 3 is a sectional view, showing how the apparatus of Figs. 1 and 2may be adapted for use with a face mask;

Fig. 4 is a perspective View showing a pressure cuff such as may beemployed around the chest of a patient in a weak, or comatose condition,to produce the air stream;

Fig. 5 is a section on the line 5 5 of Fig. 4;

Fig. 6 is a sectional View of a piece of apparatus built according tothe present preferred embodiment of this invention; and

Fig. 7 is a sectional View of a disposable combined container andinhaler made according to one embodiment of this invention.

Fig. 1 shows a Very simple form of apparatus constructed according tothis invention for administering a powdered therapeutic agent. Here, Iiidenotes a container that may be made of glass or of a suitable plastic.The open end of this container is closed by a rubber stopper ll. Thisstopper has two holes in it. Through one of these holes there passes atube l2, which extends downwardly a considerable distance into thecontainer. This tube is formed exteriorly oi the container with anenlarged portion forming a chamber lli, and beyond this chamber the tubeterminates in a reduced end portion l5. The tubular end I6 of a suitablerubber air pressure bulb Il may be connected to the end l5 of the tubeas shown in Fig. 1. Through the other hole in the stopper Il, therepasses a tube 29, which has its end turned at an angle below the stopperl I, as denoted at 2 l. Exteriorly of the container, this tube 2Q isformed with an enlarged portion 22, and it terminates in a reduced endportion 23. The enlarged portion 22 of the tube 2? has an opening 24formed in one side thereof, to provide an air vent. The tubes l2 and 2emay be made of glass, or of plastic, or of a suitable metal, such ascopper.

The therapeutic agent, which is to be used, which may be, for instance,finely powdered penicillin, whose particulate size is one micron orless, or which may be powdered penicillin mixed with powdered glucose orstarch in the form of a micropulverized powder, is placed in thecontainer l0, being denoted at P. A suitable dehydrating substance, suchas anhydrous calcium sulfate, denoted at D, is placed in the chamber I4of tube I2. This preferably is employed in the commercial form in whichit is mixed with a litmus agent so that it will turn from blue to pink,when it has picked up all the moisture which it can.

In use, if a person wants to administer the penicillin, or othertherapeutic agent to a patient, or if the patient wishes to administerit to himself, the end 23 of tube 2U may be placed one nostril of thepatient, and the bulb l1 is alternately squeezed and released. Thus, astream of air, is forced through the dehydrating substance D, downthrough the tube i2 into the container l0. The pressure of this air,forces the powder P in the container up through the substance to apatient.

secured to it at any suitable point.

fats-afoot tube 520 and 'ou-t through the end 23 this tube fa -forinlike smoke; and the patient inhal'es this therapeutic smoke. A baffle 25is secured in any vsuitable manner Vto the tube i2 some distance abovethe lower end thereof, so as to prevent the powder P from being expelledfrom the container in lumps or gobs. These might irritate the throat,and would be wasteful of the medicine. The baffile isl'circular andthere is but a -slig-ht diierence 'between the diameter of the baiileand the internal diameter of the container, so that the only vway inwhich the particles of powdered penicillin `can lreach the tube 26 isaround the periphery of Ythe baille.V

The Vent 24 in the tube 2t admits of Jan additional `current of airbeing drawn `into the tube 26 as thestream of powder and air passesthrough that tube. This additional air stream serves to keep lthe powderstirred up and agitated and `further insures that it will pass out ofthe end '23 of the tube 28 in the desired form of smoke.

Il 'the Vent were not provided, too much powder might be expelled fromthe end 23 of the vtube atone time; and this would be wasteful.

The same piece of apparatus shown in Fig. l can be used without changefor inhaling the penicillin, or other therapeutic agent, through themouth. Thus, after removing the tube It 'and air pressure bulb il, thepatient, part of whose head is denoted at H in Fig. 2, can place the end23 of the tube '26 in his mouth M and vsuck Iair through the end i5 ofthe tube i2, through the dehydrating substance D, into the container H3,and thence draw the vpowder suspended in air through the tube 2t intohis mouth. In this case, an additional current of air is usually `notrequired, and the patient can close the vent 24with his thumb.

`The same piece of apparatus can be used, also,

without substantial change, in connection with a face mask where it isdesirable to employ `such a mask in the administration of a rtherapeuticIn this case, the end 23 o f tube 23 is inserted into an opening Vformedon the projecting portion 36 of the face mask M (Fig. 3), and there is arubber fla-p valve 3! 4applied over the end 23 of tube 26. The face maskitself, which is shaped to t the contour of the face, has a furtherrubber iiap valve 32 The rubber 'ap valve 3l permits or" the powderedpenicillin and air being drawn into the face mask as the patientinhales. It closes when the patient ex- The rubber flap valve 52 yallowsof the air being exhausted from the mask when the patient 'exhales lWhena patient is in a weak or comatose condition, or lacks the power ofcoordination, the

"air pressure for forcing the powder out of the container may besupplied by the movement of "the patients chest `as he alternatelyinhales and exhales. Thus, a pressure cud, such as denoted atS in Fig.4, may be fastened around the chest of the patient by webbed straps 35and 36. These straps are secured to opposite ends of the l.pressure cuand may be fastened together at )valve litl mounted therein. which` isnormally pressed to closed 'position by la 'coil spring 4'2. The tube 39is adapted to have its vend 53 -con'- nected to the end l5 of the tubet2 of the appa ratus shown in Fig. l, in place of 'the tube i6 and airpressure bulb Il. This tube `r39 hfas a `ball check Valve fili mountedtherein, which is adapted to be pressed to closed position by a coilspring 55.

The pressure cuff is adapted to be secured 'to the patient when thepatients chest is fully expanded, that is, at full inspiration, and whenVthe springs 3l are fully collapsed by the pressure of the patientschest on the pressure cuil. `As the patient eXhales, the springs expand,'and the Valve lil opens, allowing the bag 35 to fill with air. When thepatient inhales, the chest expands; the valve El is closed; and the airis forced out of the bag 35 through the valve '41%, which is opened bythe pressure of this air, and into the end l5 of tube i2. Thus, themovement of the patients chest will'operate the apparatus of thisinvention and supply him with the lthere;- peutic agent in the form ofsmoke so that he can inhale it into his lungs. A nose clip may benecessary to secure the end 23 of the tube 4'2G in position so that thepatient can lbreathe ythe smoke in through his nose.

The present preferred form of apparatus for dispensing therapeuticsubstances according to the invention is disclosed in Fig. 6. This oom'-prises a tube 50 made of glass or plastiofone end of which is closed bya bottom cap piece 5|. If the tube 55 is made of plastic, this cap piecemay be made of plastic, also, and it may be secured in the tube 5i!simply by friction. Secured in the tube 50 by friction or in any othersuitable manner, about midway of the height of the tube is a partitionmember 52. This divides the tube 50 into a lower and an upper chamber.The lower chamber is adapted to contain the vdehydrating agent D. Thepartition member 52 has a lcentral opening or duct 53 formed therein. Ontop of the partition member 52, there is placed a thin layer of ne glasswool 513 which acts as a filter. On top of this layer of glass wool,within the 'tube 50, there is mounted a cup-shaped member 55. This isadapted to hold the powdered therapeutic agent P. There are severalequi-spaced holes 56 drilled longitudinally in the sidewall of thecup-shaped member 55 from the bottom 'of the cup-shaped member upwardlyfor the greater portion of the height thereof. These holes or ducts 56communicate with short, helically arranged ducts 51, which lead into theinterior of the cup. There is a gasket 58 placed on top of the cup 55,and the cup is secured in the tube 50 by the upper cap member it whichthreads into the tube 5i). The cap member 6e has a central openingtherein, and in this there is mounted a short tube or duct 6l. Thebottoms oi the cap member 60 and of the tube 5| are made to sphericalshape, as denoted at 62, so as to provide a dome-like or sphericaltopfor the chamber in which the powder P is contained.

There is a right angular duct drilled or otherwise formed in the bottomend cap 5|, and there is a short .tube 66 mounted at one side in thisend cap to communicate with the duct 65. An air pressure bulb 6l, havingan engaging portion 68 may be secured to the tube 65, by pushing theportion 68 over the outside of the tube 66.

To use the apparatus of Fig. 6, the patient alternately squeezes thenreleases the bulb 6?, thissforces air through the tube` 66, :and duct`6,5

into the lower chamber containing the dehydrating substance D. Thedehydrating substance removes the moisture from the air. The dried airpasses out of the lower chamber through the duct 53 in the partitionmember 52, and through the filter 54 into the ducts 5e formed in thecupshaped member 55. Thence it flows through the ducts into the interiorof this cup. The helical inclination of the ducts 57 causes air flowinginto the upper chamber to create a turbulence and force the powder intoa spiral path. The spherical dome 62 of the upper chamber helps keep thepowder agitated. From the upper chamber the air-borne powder is forcedupwardly through the opening in the tube 6| to the outer air where itemits in the form of smoke.

The upper chamber of the apparatus is of reduced area because of the useof the cup 55. The small surface area increases the emptying einciencyof the powder chamber. The outlet tube BI is likewise made of smallinternal calibre to reduce the amount of precipitate on the walls ci thetube. The threaded connection of the upper end cap 6U with the tube 50prevents the powder from seeping out between the tube 5B and the endcap, the thread serving, therefore, as a seal.

The apparatus shown in Fig. 6v is adapted to all the various uses of theapparatus shown in Figs. 1 to 5 inclusive. On removing the bulb 67, theoutlet tube 6i can be placed in the mouth, and the powder drawn directlyinto the oral cavity. The outlet tube 6i can also be connected to a facemask, in a manner similar to the connection between the outlet tube 2Bof Fig. 3 and the face mask of that gure, or, if desired, the outlettube 6l can be replaced by a right angular tube for this purpose. Thebulb 6'! can be replaced by a pressure cuff, such as shown in Figs. eand 5. Various adapters can also be tted to the outlet tube, for nasal,oral, dental, vaginal use, etc., if desired.

In some cases it may be desirable to provide an inhaler which contains asingle dose of the therapeutic agent, which is to be administered, andwhich is disposable after use. Such an inhaler is shown in Fig. '7. Thiscomprises a cylindrical-shaped cup or barrel it, and a cap il.

The cup or barrel is hollowed out to receive a measured dose of thetherapeutic powder P. Ducts 'l2 are formed in the sidewall of the cup orbarrel from the bottom 'i3 thereof to a point above the level of thepowder P in the container. These ducts 'I2 communicate with helicalducts M that lead into the interior of the container above the level ofthe powder.

The cap l l, which tapers externally upwardly, has a single axial ductl5 formed therein.

The barrel and cap may be made of papiermache or of a suitable plastic.The measured dose is placed in the container and the cap sealed thereon.Then container and cap are dipped in some suitable sealing material orwrapped in a suitable cellulose cover so as to completely seal and coverthe whole container. This sealing covering is designated at 76 in Fig.'7. Strings or wires 11 and 'i8 may be embedded in this covering so thatwhen they are pulled, the part of the covering, which covers the outsideend of duct l5, and the part of the covering, which covers the bottom oroutside ends of ducts l2, are removed. Then the inhaler is ready foruse` In use, the patient simply puts the small end of the cap 'Il into anostril or into his mouth and inhales. Air is drawn through the ducts 12and 'I4 into the powder chamber; the helical shape of the ducts createsa turbulence in the powder; and the powder in suspension is drawn upthrough the duct 15 into the nostril or mouth.

The principle of administering soluble, absorbable therapeutic agents ina micro-pulverized state, suspended in air with or without a vehicle, byinhallation is a new method of therapeutics. It may be applied topenicillin in the crystalline or amorphous state. It may be used asalready indicated for the administration of any other absorbabletherapeutic agent such as streptomycin and the sulfonamides, eitherseparately or in combination. All of the antibiotic agents such as thesulfonamides, and streptomycin are now available in crstalline form; andin the crystalline state they are stable so long as they are kept inmoisture-free containers. In addition, the invention may be used for theadministration of insulin and other hormones, such as estrone,progesterone, testosterone, desoxycorticosterone, or for theadministration of any of the antihistamine group of drugs in thetreatment of hay fever, hives, etc., or in the administration ofpituitrin, or of the vasoconstrictors, such as Neosynephrina Tuarnine,adrenalin, ephedrin, Privin'e, Paredrine, etc., or it may be used in theapplication of heparin. In case of administration of drugs of theantihistamine group, the present invention is much more eiective thanprevious methods of treating hay fever and other allergies throughhypodermic injections. With the method of the present invention thetherapeutic agent is supplied directly to the nose and lungs, and doesnot have to be absorbed into the blood stream to begin to work.

The above named drugs can be given individually or in combination asindicated, and may be combined in a vehicle which will allow eitherrapid or slow absorption as desired. The drugs furthermore, may becombined with the vehicle either physically or chemically, and manycombinations may be devised to t particular needs.

The equipment and therapeutic agent may also be used for topicaladministration, such as for dusting open wounds, burns, otitis externa,abdominal wounds, vaginal and rectal infections, surgical wounds, etc.;and the use of the method and apparatus is not limited to inhalationprocedures alone. Heretofore, for instance, in administering penicillin,streptomycin, tyrothricin, and similar substances to open wounds, theyhave simply been thrown into the wound. With the apparatus and method ofpresent invention, the substance can be applied more thoroughly to thewound or burn, and more efciently. The smoke penetrates to every part ofthe area to be treated and is much more effective than merely scatteringthe therapeutic agent over the surface.

There are certain diseases in the treatment of which this new method -oftherapy is particularly advantageous. In principle, they are thediseases where a high concentration of therapeutic agent at the surfaceof the infection or reacting organ is of special importance. Thus, thepresent method of therapy may be used in the treatment of diseases ofthe respiratory tract caused by organisms sensitive to the availableantibiotics including such diseases as: tonsillitis, Vincents angina,infected tooth sockets, diphtheria, otitis media, sinusitis, laryngitis,tracheitis, bronchitis, pneumonia, bronchiectasis, and tuberculosis.Moreover, the invention is applicable in cases of disease carriers,particularly in such cases as meningococcus, Streptococcus, diphtheria,and pneumococcus. It may be used.

also, in the treatment of urinary infection particularly by use ofstreptomycin.

In addition, the principle of treatment involved in this inventionprovides a means of admnistration of various therapeutic agents that canbe used on ambulatory patients for the venereal diseases such asgonorrhea, syphilis, chancroid, and lymphagranuloma. It can also be usedfor treatment of rheumatic fever. In this last-named case, sulfonamidesor penicillin may be continuously administered for treatment ofhemolytic streptococcal infections. The invention may be employed, also,in the treatment of meningitis, scarlet fever, pneumonia, diphtheria andstreptococcal diseases in hospitals, barracks, and closely-knitcommunities; and for the prevention of post-operative pulmonaryinfections by pre-operative sterilization of the respiratory tract byuse of the various antibiotics singly or in combination as indicated bythe bacterial flora present.

This invention provides a ynew principle of therapeutics through whichnumerous specific drugs may be administered in micro-pulverized state,suspended in air, with or without a vehicle. The apparatus constructedaccording to the invention is simple to operate, inexpensive, enicient,fool-proof, and measured doses of various therapeutic agents may beadministered by it in the hospital or at home in a period of two to veminutes without any of the disadvantages of the previous method ofadministration of such substances.

While the invention has been described in connection with particularembodiments and particular uses thereof, it will be understood that 1tis capable of various further modifications and uses, and that thisapplication isl intended to cover any variations, uses, or adaptationsof the invention following, in general, the principles of the inventionand including such departures from the present disclosure as come withinknown or customary practice in the art to which the invention pertainsand as may be applied to the essential features hereinbefore set forthand as fall within the scope of the invention or the limits of theappended claims.

Having thus described our invention, what we claim is:

1. A therapeutic agent for direct administration to humans by inhalationcomprising dry, micropulverized, powdered penicillin having aparticulate size in the order of one micron.

2. A therapeutic agent for direct administration to humans by inhalationcomprising a dry,

1o micropulverized, powdered, soluble antibiotic substance, from thegroup consisting of penicillin and streptomycin which are produced bymicroorganisms, the particulate size of the micropulverized substancebeing in the order of one micron.

3. A therapeutic agent for direct administration to humans. byinhalation comprising dry, micro-pulverized, powdered streptomycinhaving a particulate size in the order of one micron.

4. A therapeutic agent for direct administration to humans by inhalationcomprising dry, micropulverized, powdered crystals of a solubleantibiotic substance, from the group consisting of penicillin andstreptomycin which are produced by micro-organisms, the particulate sizeof the micropulverized crystals not exceeding one micron.

5. A therapeutic agent for direct administration to humans by inhalationcomprising a dry, micropulverized, powdered mixture of glucose and asoluble antibiotic substance from the group consisting of penicillin andstreptomycin which are produced by micro-organisms, the particulate sizeof said mixture being in the order of one micron.

GEORGE V. TAPLIN. FREDERICK A. BRYAN.

REFERENCES CITED The following references are of record in the le ofthis patent:

UNITED STATES PATENTS Number Name Date 236,071 Olcott Dec. 28, 18802,156,378 Denny et al. May 2, 1939 2,185,927 Shelanski Jan. 2, 19402,214,032 Stewart Sept. 10, 1940 2,414,918 Abramson Jan. 28, 1947 OTHER,REFERENCES Surgery, Dec. 1944, pages 937 and 938.

The Pharmaceutical Journal (London) Feb. 8, 1941, page 40.

Science, July 14, 1944, pages 33-35.

Science, Sept. 7, 1945, pages 255 and 256.

J. A. M. A., May 23, 1942, pages 324 to 327.

J. A. M. A., Apr. 25, 1942, page 1514.

Proc. Soc. Exptl. Biol. and Med., Oct. 1943. pages 8 to 10.

British Medical J., Aug. 16, 1941, page 221.

Int. Abstract Surgery, July 1943, pages 79 and 80.

The Lancet (London), Dec. 16, 1944, page 775.

1. A THERAPEUTIC AGENT FOR DIRECT ADMINISTRATION TO HUMANS BY INHALATIONCOMPRISING DRY, MICROPULVERIZED, POWDERED PENICILLIN HAVING APARTICULATE SIZE IN THE ORDER OF ONE MICRON.